Stem cell failure may play a significant role in human aging. Aging results from a complex set of cellular and physiological interactions and feedbacks between multiple biological systems. In the past 10 years specific genetic and cellular pathways have been identified in model organisms and in cultured cells that play important roles in aging. The contribution and intersection between these specific pathways is not yet clear. Stem cell failure is one model that may help reconcile the multiple primary causes of aging. Stem cell function is essential for tissue homeostasis and renewal and their loss may explain the multi-system failure that occurs in aging. Telomere length can limit cellular lifespan. Telomeres shorten progressively in primary cells that lack the enzyme telomerase, and even in some cells that do express telomerase. The genetic disease dyskeratosis congenita is an example of a premature aging syndrome that likely involves stem cell failure. Patients with this disease exhibit phenotypes associated with aging including premature graying, hair loss, osteoporosis, increased malignancy, immune dysfunction, chemotherapy intolerance and decreased bone marrow cellularity. It is the bone marrow failure, or aplastic anemia, that leads to death in these patients. Both dyskeratosis congenita and constitutional aplastic anemia are linked to mutations in the telomerase RNA component. We have generated a line of telomerase RNA null (mTR-/-) mice on the CAST/EiJ genetic background that has short telomeres, similar to telomere length in humans. Preliminary analysis of this mouse indicates that telomere shortening leads to loss of stem cells, and organ failure. Both the first and second-generation CAST/EiJ mTR-/- mice have shortened lifespans. Further, late generation heterozygous CAST/EiJ mTR mice also show telomere shortening and stem cell failure. This provides genetic evidence for haploinsuffiency of telomerase RNA. The experiments proposed here will address directly whether short telomeres cause stem cell loss and establish the consequences of the telomere shortening in specific tissues. [unreadable] [unreadable]